1. Field of the Invention (Technical Field):
The present invention relates to tetra- and penta-substituted piperazine and piperazine-derivative ring compounds, the ring compounds optionally including one C═O or C═S member, that bind to one or more melanocortin receptors and are optionally agonists, antagonists, mixed agonist-antagonists or inverse agonists with respect to one or more melanocortin receptors, and use thereof for the treatment of metabolic, immune, infection-related and melanocortin receptor-mediated disorders.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Piperazines are an important class of molecular templates that have been employed in the development of several drugs. However, in the prior art generally only mono- or di-substituted piperazine templates have been employed. In a few instances a tri-substituted piperazine has been employed, such as indinavir (Merck), an HIV protease inhibitor drug that incorporates a tri-substituted piperazine.
Melanocortin Receptor-Specific Agents. A family of melanocortin receptor types and subtypes have been identified, including melanocortin 1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin 2 receptors (MC2-R) for adrenocorticotropin (ACTH) expressed in cells of the adrenal gland, melanocortin 3 and melanocortin 4 receptors (MC3-R and MC4-R), expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin 5 receptors (MC5-R), expressed in a wide distribution of tissues.
In general, compounds specific for MC1-R are believed to be useful for treatment of melanoma. Compounds specific for MC3-R or MC4-R are believed to be useful in regulation of energy homeostasis, including use as agents for attenuating food intake and body weight gain, for use in treatment of anorexia and cachexia, for treatment of obesity, and treatment of other food intake and metabolism-related indications. Compounds specific for MC3-R and MC4-R, among other melanocortin receptors, can further be used as agents for treatment of sexual dysfunction, including male erectile dysfunction. Other clinical uses are being explored, such as use of MC4-R antagonists as anxiolytic or antidepressant drugs. Other melanocortin receptor-specific compounds, such as MCR-1 agonists, can be used as tanning agents to increase melanin production in the skin, acting as chemo-preventive agents against harmful effects of UV solar radiation. Compounds specific for MCR-1 and MCR-3 may further be useful in regulation of inflammatory processes. Compounds specific for MCR-5 may be used for treatment of acne and related skin disorders due to over stimulation of sebaceous gland. Compounds specific for MCR-4 and MCR-5 may be used for treatment of depression. Compounds specific for MCR-3 may find use as a therapeutic for treating salt-induced hypertension. In general, the melanocortin system is involved in diverse physiological functions, including energy balance, pigmentation, sexual function and inflammation.
The mechanism of action of compounds specific for MC3-R or MC4-R as agents for attenuating food intake and body weight gain has not been fully elucidated. While most reports suggest that MC4-R agonists may be employed for attenuating food intake and body weight gain, it is clear that agouti-related protein (AgRP), an endogenous inverse agonist, plays a critical role in the regulatory system. At least one group has suggested that a neutral antagonist of AgRP may produce agonist-like effects in vivo. (Adan, R. A. H. and Kas, M. J. H. Inverse agonist gains weight. TRENDS in Pharmacological Sciences 24(6):315-321, 2003.) However, no such compounds have heretofore been described. Further, all or virtually all MC4-R agonists compounds reported for attenuating food intake or body weight gain in animal models have shown a “rebound” effect, with animals gaining weight equal to or, in most instances, exceeding controls on cessation of administration of the compounds. There is thus a need for compounds which attenuate food intake or body weight gain without causing a rebound effect on cessation of administration of the compound.
There is a significant need for compounds with high specificity for discrete melanocortin receptors, as well as for compounds that are agonists, inverse agonists, antagonists, or otherwise bind to specific melanocortin receptors. High affinity compounds for melanocortin receptors can be used to exploit varied physiological responses associated with melanocortin receptors, as agonists, antagonists, inverse agonists or otherwise. In addition, melanocortin receptors have an effect on the activity of various cytokines, and high affinity compounds for melanocortin receptors can be used to regulate cytokine activity.
Piperazine Compounds. There are piperazine and piperidine compounds known, such as those disclosed in WO 03/009850 (Amgen), WO 03/009847 (Amgen), WO 03/094918 (Neurocrine Biosciences), WO 03/1093234 (Procter & Gamble), WO 03/092690 (Procter & Gamble), WO 03/061660 (Eli Lilly and Company), WO 03/053927 (Taisho Pharm.), WO 03/031410 (Neurocrine Biosciences), WO 03/007949 (Merck & Co.), WO 02/092566 (Taisho Pharm.), WO 02/079146 (Bristol-Myers Squibb Company), WO 02/070511 (Bristol-Myers Squibb Company), WO 02/068388 (Merck & Co.), WO 02/068387 (Merck & Co.), WO 02/067869 (Merck & Co.), WO 02/059095 (Eli Lilly and Company), WO 02/00259 (Taisho Pharm.), and WO 00/74679 (Merck & Co.), asserted to be specific for melanocortin or related receptors. However, in general such compounds have at most two functional substituted groups, have relatively poor affinity and specificity, and are not suitable for use as a drug compound. There is a significant need for compounds with high specificity for discrete receptors, such as specific melanocortin receptors, as well as compounds that are agonists, inverse agonists, or antagonists for such receptors. High affinity compounds for such receptors can be used to exploit varied physiological responses associated with the receptors, either as agonists or antagonists. There is thus a need for compounds that are more selective, including higher affinity and specificity, and in particular for compounds that have at least four biologically active substituted groups. This invention addresses that need.
WO 02/085925, “Melanocortin Receptor Ligands”, to The Proctor & Gamble Company, discloses ketopiperazine structures and methods of synthesis thereof, but does not disclose piperazine structures, piperazine structures with four substituted groups, methods to synthesize piperazine structures, methods to synthesize piperazine or ketopiperazine structures with four substituted groups, or methods to synthesize optically pure structures, and further does not disclose structures with a single substituent group that is a single D-Phe residue, or a derivative or homolog thereof, optionally with an amine capping group.
With respect to certain objects, methods, synthetic schemes, utilities, applications, definitions, protocols and other disclosures, this application is related to PCT/US02/25574, entitled Peptidomimetics of Biologically Active Molecules, filed on Aug. 12, 2002; to PCT/US01/50075, entitled Identification of Target-Specific Folding Sites in Peptides and Proteins, filed on Dec. 19, 2001; and to U.S. patent application Ser. No. 10/762,079, entitled Piperazine Melanocortin-Specific Compounds, filed on Jan. 20, 2004; and the specifications of each of the foregoing are incorporated herein by reference as if set forth in full.